Molecular mechanisms controlling skin heterogeneity

控制皮肤异质性的分子机制

• 批准号: 10669251
• 负责人: Sarah E. Millar
• 金额: $ 56.37万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669251
• 关键词: ATAC-seq; Acne; Address; Adipocytes; Adult; Affect; Area; Candidate Disease Gene; Cells; Characteristics; Chromatin; Chromatin Structure; DNA Methylation; DNA Modification Process; Data; Dermal; Dermis; Development; Disease; Dorsal; Ear; Embryo; Embryonic Development; Enhancers; Epidermis; Epigenetic Process; Experimental Genetics; Extensor; Fetal Development; Fibroblasts; Gene Deletion; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genetic study; Growth; Hair; Hair follicle structure; Heterogeneity; Hi-C; Histology; Human; Leg; Life; Location; Maintenance; Male Pattern Baldness; Molecular; Multiomic Data; Mus; Natural regeneration; Nature; Palmoplantar Keratosis; Pathway interactions; Pattern; Phenotype; Pigmentation physiologic function; Population; Psoriasis; Quality of life; Rare Diseases; Repression; Sampling; Scalp structure; Signal Transduction; Site; Skin; Skin graft; Sweat Glands; System; Testing; Therapeutic; Thick; Tissue-Specific Gene Expression; Variant; Vitiligo; XCL1 gene; bisulfite sequencing; candidate identification; cell type; comparative; density; differential expression; experimental study; face skin; fetal; genetic analysis; hair regeneration; histone modification; improved; in vivo; inhibitor; loss of function; mouse genetics; mouse model; multiple omics; nerve supply; new therapeutic target; novel; postnatal; programs; regional difference; response to injury; single cell analysis; single-cell RNA sequencing; skin disorder; skin organogenesis; therapeutic target; tongue papilla; tool; transcription factor; transcriptome sequencing; wound healing

Different regions of the skin vary in their characteristics such as thickness, pigmentation, innervation, and presence, size and density of hair follicles and sweat glands, that are reflected in differential responses to injury and disease. As examples, androgenetic alopecia is limited to the scalp; acne predominates in facial skin; psoriasis is often most prominent in extensor regions; palmoplantar keratoderma is limited to palms and soles; and vitiligo can appear in symmetrical patterns. While regional characteristics of the skin are established during fetal development, positional information must be retained in the skin throughout life to allow for maintenance of regional characteristics and their re-establishment in wound healing. Positional information is known to reside in the skin dermis, but its molecular basis is poorly understood. To address this question, we propose the following Specific Aims. AIM 1: To identify candidate factors and areas of chromatin involved in establishing skin heterogeneity in embryogenesis we will analyze transcriptional profiles through single cell RNA-seq, and chromatin structure via single cell ATAC-seq, in distinct regions of developing skin to identify those that show region-specific expression or openness, respectively. AIM 2: (i) To determine which of these candidate factors and chromatin areas may also be responsible for maintaining regional skin heterogeneity in adult life, we will perform the same analyses on the corresponding areas of adult skin. (ii) We hypothesize that epigenetic mechanisms contribute to maintenance of regional skin characteristics. To test this, we will first identify patterns of DNA methylation and histone modifications that characterize developing dermis in specific skin regions by carrying out Bisulfite-seq to reveal sites of DNA methylation, and CUT&RUN for histone modifications that mark enhancers and active, repressed, or poised genes. We will then ask which of these patterns are maintained in adult dermal cells from the same regions. AIM 3: To test the functions of candidate regulators in directing and maintaining region-specific differentiation programs, we will use inducible genetic tools to delete the corresponding genes in developing or adult mouse dermis in vivo. Together, these experiments provide a comprehensive and unbiased approach to identify novel mechanisms that establish and maintain skin heterogeneity. Improved understanding of these mechanisms has potential to reveal new therapeutic targets in wound healing and in common and rare diseases that affect specific skin regions and have a major negative impact on quality of life; data obtained in this project will also inform strategies for generating specific skin types, including hair follicle- and sweat gland-bearing skin, for reparative skin grafting.

皮肤的不同区域有不同的特征，如厚度、色素沉着、神经支配和 毛囊和汗腺的存在、大小和密度，反映在对 受伤和疾病。例如，雄激素性脱发仅限于头皮，面部以粉刺为主。 皮肤；银屑病通常最突出的是伸肌区；掌足部角化皮病仅限于手掌和 鞋底；白癜风可以以对称的图案出现。同时建立了皮肤的区域特征 在胎儿发育期间，位置信息必须在整个生命周期内保留在皮肤中，以便 伤口愈合中地域特征的保持和重建。位置信息是 已知存在于皮肤真皮中，但其分子基础尚不清楚。为了解决这个问题，我们 提出以下具体目标。目标1：确定与染色质有关的候选因素和区域 建立胚胎发育中皮肤的异质性，我们将通过单细胞分析转录图谱 RNA-seq和染色质结构通过单细胞atac-seq，在皮肤发育的不同区域进行鉴定 那些分别表现出特定地区表达或开放性的。目标2：(I)确定以下哪一项 候选因素和染色质区域也可能是维持局部皮肤异质性的原因。 在成人生活中，我们将对成人皮肤的相应区域进行同样的分析。(Ii)我们假设 表观遗传机制有助于维持局部皮肤特征。为了测试这一点，我们首先 确定DNA甲基化和组蛋白修饰的模式，以表征特定的发育中的真皮 皮肤区域进行亚硫酸氢盐序列以揭示DNA甲基化位点，并切割和运行组蛋白 标记增强剂和活性、抑制或稳定基因的修饰。然后我们会问这些中的哪一个 在来自相同区域的成人真皮细胞中也保持着这种模式。目标3：测试考生的功能 在指导和维护特定区域的分化计划时，我们将使用可诱导基因 在体内删除发育中或成年小鼠真皮中的相应基因的工具。加在一起，这些 实验提供了一种全面和不偏不倚的方法来确定建立和 保持皮肤的异质性。对这些机制的更好理解有可能揭示新的 伤口愈合以及影响特定皮肤区域和特殊皮肤的常见病和罕见病的治疗靶点 对生活质量有重大的负面影响；在这个项目中获得的数据也将为 产生特定的皮肤类型，包括毛囊和汗腺皮肤，用于修复性皮肤移植。